PROJECT SUMMARY/ABSTRACT The proposed project investigates the effects of experimental sleep disruption (SD) on opioid response in males and females with chronic low back pain (CLBP). We propose that SD will alter two primary factors strongly related to problematic opioid use: 1) measures of opioid abuse liability (self-report indices of ?how high? the drug makes you feel, ?drug liking? and the monetary valuation of the drug after acute opioid administration) and 2) opioid analgesic efficacy. We expect these responses will be more pronounced in chronic low back pain (CLBP) vs. healthy controls, and in males to a greater extent than females. Our preliminary data show that SD operates on several intermediate factors associated with both opioid abuse liability and analgesia, including positive affect, pain sensitivity, and the function of the ventral striatum, the hub of the brain reward system. Extant literature suggests that CLBP patients may be especially vulnerable to these effects due to abnormal reward system neurocircuitry. The evaluation of sex differences in these relationships is essential because males and females evidence different risk profiles with respect to opioid addiction, sleep problems, and pain. The next step is to directly evaluate the effect of SD on opioid response in these groups. We propose a within/between design in which male and female participants with CLBP (N=60) and healthy controls (N=60) will experience both one night of SD and one night of normal sleep, in a random order. Following each sleep condition, we will evaluate the opioid abuse liability and analgesic efficacy of hydromorphone, a short-acting synthetic opioid with strong affinity for the ?-opioid receptor, in a placebo- controlled cumulative dose run-up paradigm. Opioid abuse liability will be assessed with measures of drug high, liking and the multiple choice procedure, which will measure the monetary valuation of the drug. Analgesia will be assessed with quantitative sensory testing involving noxious thermal stimuli. We hypothesize that opioid abuse liability will be augmented and analgesia diminished by SD. We expect those effects to be stronger in patients with CLBP than healthy controls. Among CLBP patients, we anticipate that males will evidence greater changes in opioid response following SD than females. This study fills a critical knowledge gap with major implications for addressing the opioid epidemic. Findings from the proposed study will inform clinical decision making related to the use of opioids for patients with chronic pain, and may lead to the development of novel interventions targeting sleep as a means to mitigating problematic opioid use. Data from the proposed project could lead to subsequent studies designed to determine the extent to which SD-induced alterations in opioid abuse liability and analgesic efficacy are mediated by putative neurobiological mechanisms (e.g., striatal function), which could themselves be targeted with pharmacological and/or neurostimulation therapies in an effort to prevent problematic opioid use.